Placental mTOR complex 1 regulates fetal programming of obesity and insulin resistance in mice

Brian Akhaphong, Daniel C Baumann, Megan M Beetch, Amber D Lockridge, Seokwon Jo, Alicia Wong, Tate Zemanovic, Ramkumar Mohan, Danica L. Fondevilla, Michelle Sia, Maria Ruth B. Pineda-Cortel, Emilyn U. Alejandro

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Fetal growth restriction, or low birth weight, is a strong determinant for eventual obesity and type 2 diabetes. Clinical studies suggest placental mechanistic target of rapamycin (mTOR) signaling regulates fetal birth weight and the metabolic health trajectory of the offspring. In the current study, we used a genetic model with loss of placental mTOR function (mTOR-KOPlacenta) to test the direct role of mTOR signaling on birth weight and metabolic health in the adult offspring. mTOR-KOPlacenta animals displayed reduced placental area and total weight, as well as fetal body weight at embryonic day (E) 17.5. Birth weight and serum insulin levels were reduced; however, β cell mass was normal in mTOR-KOPlacenta newborns. Adult mTOR-KOPlacenta offspring, under a metabolic high-fat challenge, displayed exacerbated obesity and metabolic dysfunction compared with littermate controls. Subsequently, we tested whether enhancing placental mTOR complex 1 (mTORC1) signaling, via genetic ablation of TSC2, in utero would improve glucose homeostasis in the offspring. Indeed, increased placental mTORC1 conferred protection from diet-induced obesity in the offspring. In conclusion, placental mTORC1 serves as a mechanistic link between placental function and programming of obesity and insulin resistance in the adult offspring.

Original languageEnglish (US)
Article numbere149271
JournalJCI Insight
Volume6
Issue number13
DOIs
StatePublished - Jul 8 2021

Bibliographical note

Funding Information:
We thank Robert Sorenson (University of Minnesota), Cyprian Weaver (University of Minnesota), David Bernlohr (University of Minnesota), Brigid Gregg (University of Michigan), Jean Regal (University of Minnesota-Duluth), and Sarah Wernimont (University of Minnesota) for discussion; Mark Sanders and Thomas Pengo (University of Minnesota University Imaging Centers) for imaging expertise; and G. Leone (The Ohio State University) for the donation of the CYP19Cre mice. Microscope and imaging support was provided by the Department of Integrative Biology and Physiology (IBP) and the University Imaging Centers (https://med.umn.edu/uic). Body composition analysis and whole-animal energy expenditure were serviced by the IBP Core. We thank Pilar Guzman for assistance with surgery. We also thank Chi Chen for his assistance in measuring AAs (University of Minnesota). This work was supported by NIH grants (R21DK112144, R21HD100840, R03DK114465, R01DK115720), Regenerative Medicine Minnesota, and IBP startup funds to EUA; Philippine Council for Health Research and Development ? Department of Science and Technology (grant MOA 18?0200 and 19?0663) to MRBPC; NIH T32 DK007203 to MB; and NIH R03DK11446501AIS1 to BA.

Funding Information:
We thank Robert Sorenson (University of Minnesota), Cyprian Weaver (University of Minnesota), David Ber-nlohr (University of Minnesota), Brigid Gregg (University of Michigan), Jean Regal (University of Minnesota-Duluth), and Sarah Wernimont (University of Minnesota) for discussion; Mark Sanders and Thomas Pengo (University of Minnesota University Imaging Centers) for imaging expertise; and G. Leone (The Ohio State University) for the donation of the CYP19Cre mice. Microscope and imaging support was provided by the Department of Integrative Biology and Physiology (IBP) and the University Imaging Centers (https://med. umn.edu/uic). Body composition analysis and whole-animal energy expenditure were serviced by the IBP Core. We thank Pilar Guzman for assistance with surgery. We also thank Chi Chen for his assistance in measuring AAs (University of Minnesota). This work was supported by NIH grants (R21DK112144, R21HD100840, R03DK114465, R01DK115720), Regenerative Medicine Minnesota, and IBP startup funds to EUA; Philippine Council for Health Research and Development — Department of Science and Technology (grant MOA 18–0200 and 19–0663) to MRBPC; NIH T32 DK007203 to MB; and NIH R03DK11446501AIS1 to BA.

Publisher Copyright:
© 2021, Akhaphong et al.

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